There are many disorders that are thought to arise from the same general mechanism based upon misfolding and aggregation of underlying proteins, including prion-related disorders, neurodegenerative diseases, and several systemic disorders. See, for example, Schluter et al. (1986) PNAS 83:6137–6141; Kannan et al. (1988) J. Biol. Chem. 263:3766–13773; Carrell and Lomas (1997) Lancet 350:134–138; Carrell and Gooptu (1998) Curr. Op. Struc. Biol. 8:799–809; Soto (2001) FEBS Letters 498:204–207; Jaikaran and Clark (2001) Biochimica et Biophysica Acta 1537:179–203; Ursini et al. (2002) Trends Mol. Med. 8:370–374; and Davis et al. (2002) Lancet 359:2242–2247.
One of the suggested mechanisms of protein aggregation is seeded polymerization, in which initial seeds nucleate the deposition of monomers. For example, aggregates of denatured hemoglobin called Heinz bodies were found in aged erythrocytes. See Schluter et al. (Supra). Further, Kannan et al. (Supra) described a protein aggregation from sickle erythrocytes that is mostly composed of globin. Particles resembling those described by Enderlein (1925) Bakterien-Cyclogenie (Verlag de Gruyter & Co, Berlin), were isolated from the blood of cancer patients and determined to be composed of mainly denatured hemoglobin (Gerner (1997) Blut. Curr. Onkol. 7:6P12).
Aggregated proteins associated with disorders are found in other biological materials, as well. For example, proteinaceous particles isolated from brain were identified as causing scrapie (Prusiner (1982) Science 216:136–144). Since then, these particles and their structure have represented important areas of study (Prusiner (1991) Science 252:1515–1522; Wille et al. (2002) Biophysical J. 82:825; Wille et al (2002) PNAS 99:3563–3568; Geschwind et al. (2002) Neurology 58:A135–A135; Dyson et al. (2002) Biophysical J. 82:824), and methods for the sensitive detection of prion-related disorders using ultrasound have been developed. See Saborio (2001) Nature 411:810–813. Recently, micrometer-sized particles were identified in the cerebrospinal fluid of patients with schizophrenia (Wetterberg et al. (2002) Neurosci Lett. 329:91–5). Accordingly, new compositions and methods for the formation, isolation, and detection of misfolded, aggregated proteins are required.